Document Detail


In vitro cytotoxicity of 2-chlorodeoxyadenosine and chlorambucil in chronic lymphocytic leukemia.
MedLine Citation:
PMID:  8946937     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic lymphocytic leukemia (CLL) is most commonly treated with the alkylating agent chlorambucil (CLB), although the nucleoside analogs, fludarabine (Flu) and 2-chlorodeoxyadenosine (CdA), are also effective in this disease. In this study, we investigated the in vitro cytotoxicity of CdA and CLB in CLL cells from 12 patients in vitro. Treatment with CLB for 6 h, followed by CdA for 18 h, resulted in 2.3- to 7.5-fold synergistic cytotoxicity in leukemic cells from 10 patients and an additive effect in cells from two patients. In general, synergy was greatest in patients who were sensitive to CLB or CdA, and could be enhanced by increasing the concentrations of CLB or CdA. Synergy was only observed if the cells were treated with CLB prior to CdA. Synergy could not be explained by an increase in the incorporation of CdA into DNA, or by the inhibition of repair of CLB-induced DNA crosslinks by CdA. In contrast to CLL cells, treatment of human marrow in vitro with CLB and CdA resulted in a low level of synergy for CFU-GM cells, and additive cell kill in erythroid progenitors. Thus, treatment with CdA and CLB can produce selective synergistic cell kill in CLL cells, and combination therapy may improve the therapeutic index of these agents in chemosensitive patients.
Authors:
A Begleiter; H Wang; L Verburg; K Lee; L G Israels; M R Mowat; J B Johnston
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Leukemia     Volume:  10     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  1996 Dec 
Date Detail:
Created Date:  1997-01-13     Completed Date:  1997-01-13     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1959-65     Citation Subset:  IM    
Affiliation:
Manitoba Institute of Cell Biology, Manitoba Cancer Treatment and Research Foundation, Canada.
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MeSH Terms
Descriptor/Qualifier:
Aged
Antineoplastic Combined Chemotherapy Protocols / metabolism,  pharmacology*,  toxicity
Bone Marrow / drug effects
Cells, Cultured
Chlorambucil / administration & dosage,  pharmacology*,  toxicity
Cladribine / administration & dosage,  pharmacology*,  toxicity
DNA Damage
DNA Repair / drug effects
DNA, Neoplasm / drug effects,  metabolism
Drug Administration Schedule
Drug Interactions
Female
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*,  metabolism
Male
Middle Aged
Tritium
Tumor Cells, Cultured / drug effects
Chemical
Reg. No./Substance:
0/DNA, Neoplasm; 10028-17-8/Tritium; 305-03-3/Chlorambucil; 4291-63-8/Cladribine

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